Formation of reactive o-quinone methides from the reaction of trimethylsilyl(methyl)-substituted 1,4-benzoquinones with nucleophiles

Article abstract of DOI:10.1016/j.tet.2004.09.052

o-Quinone methides are formed from the reaction of nucleophiles with trimethylsilyl(methyl)-1,4-benzoquinones. These reactive intermediates are trapped by excess nucleophile to form substituted quinones following oxidation. In addition, varying amounts of a symmetrical dimer and a xanthen derivative were observed. The influence of different nucleophiles and ring substituents on the rate of reaction have been studied, and are consistent with rate-limiting formation of a vinylogous enolate initiated by attack of the nucleophile on the silyl group. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.09.052

Tetrahedron 61 (2005) 275–286
Formation of reactive o-quinone methides from the reaction of
trimethylsilyl(methyl)-substituted 1,4-benzoquinones with
nucleophiles
*
John E. Ezcurra, Kostas Karabelas and Harold W. Moore
Department of Chemistry, 516 Rowland Hall, The University of California, Irvine, CA 92697, USA
Received 18 June 2004; revised 15 September 2004; accepted 16 September 2004
Available online 5 November 2004
Abstract—o-Quinone methides are formed from the reaction of nucleophiles with trimethylsilyl(methyl)-1,4-benzoquinones. These reactive
intermediates are trapped by excess nucleophile to form substituted quinones following oxidation. In addition, varying amounts of a
symmetrical dimer and a xanthen derivative were observed. The influence of different nucleophiles and ring substituents on the rate of
reaction have been studied, and are consistent with rate-limiting formation of a vinylogous enolate initiated by attack of the nucleophile on
the silyl group.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
xybenzyl alcohols and the fluoride-induced desilylation of
silylated o-hydroxybenzyl bromide (XZBr) and bis-sil-
ylated o-hydroxybenzyl alcohol (XZOH).6 Other methods of
note involve oxidation of o-alkyl-substituted phenols and the
thermal ring expansion of 4-allenyl-4-hydroxycyclobute-
nones.7,8 Reported herein is a new method for the generation
of o-quinone methides from (trimethylsilylmethyl or triar-
ylsilylmethyl)-1,4-benzoquinones. This involves treatment of
(trialkylsilylmethyl or triarylsilylmethyl)-1,4-benzoquinones
with oxygen-nucleophiles such as alcohols or water. The
reaction conditions are mild and the transformation can be
accomplished under neutral conditions.9
The formation of o-quinone methides as reactive intermedi-
ates in biologically-active natural products has been
reviewed.1 For example, a proposed reactive quinone
methide intermediate generated from the naturally occur-
ring antitumor antibiotic, mitomycin C, is believed to be
responsible for DNA alkylation.2 Similarly, a quinone
methide has been detected to arise from daunomycin and
shown to function as an alkylating agent.3 Apart from their
involvement in biological processes, o-quinone methides
have proven useful as synthetic intermediates. For example,
electrophilic o-quinone methides of structural type 3 react
with a variety of nucleophiles (Michael addition), resulting
in substituted hydroquinones.4 They also function as
efficient heterodienes in Diels–Alder reactions and undergo
a variety of self dimerization reactions.5
A generalized mechanistic paradigm to account for the
reaction is outlined in Scheme 2. The appropriately
substituted quinone 4 reacts with nucleophiles to generate
vinylogous enolate 5, which provides o-quinone methide 6
upon silylation. The resulting o-quinone methide reacts
further with the nucleophile to form substituted hydro-
quinone 7, which is readily oxidized to the corresponding
substituted quinone. Details of this study including synthetic
applications and mechanistic details are now provided.
A common method for the generation of o-quinone methides
3 from appropriately substituted quinones, 1, is initiated by
their reduction to the corresponding hydroquinone 2
followed by intramolecular elimination of an equivalent of
HX to form the o-quinone methide (Scheme 1). Variations of
this method include the thermal dehydration of o-hydro-
Keywords: o-Quinone methide; 1,4-benzoquinones; Trimethylsilyl;
Michael addition; Diels–Alder; Dimerization.
* Corresponding author at present address: Transmolecular, Inc. One
Perimeter Park South–Suite 400 North, Birmingham, AL 35243, USA.
Tel.: C1 205 943 6732; fax: C1 205 943 6734;
e-mail: ezcurra@transmolecular.com
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.052

276
J. E. Ezcurra et al. / Tetrahedron 61 (2005) 275–286
Scheme 2.
2. Results and discussion
along a minor amount (5%) of the symmetrical dimer 11a
(R1ZR2ZOMe). The symmetrical dimer 11a may be
envisaged to arise via a number of possible pathways. For
example Diels–Alder dimerization of two o-quinone
methides would result in a spiropyran. Subsequent ring
opening would then provide the dimer in its half reduced
form. Oxidative work up leads to 11a. An alternate route
would provide the half reduced dimer via Michael addition
A set of reactions illustrating the intermediacy of the o-
quinone methides is outlined below (Scheme 3). When an
ethanolic solution of quinone 9a (R1ZR2ZOMe, R3ZMe)
was refluxed for 45 min then worked up under oxidative
conditions (Ag20), the corresponding ethoxymethyl quinone
10a (R1ZR2ZOMe, R4ZEt) was isolated in 82% yield
Scheme 3.

J. E. Ezcurra et al. / Tetrahedron 61 (2005) 275–286
277
of the enolate to the o-quinone methide. At ambient
temperature the reaction required 24 h and the above
products were realized in 45 and 22%, respectively. In
comparison, when the amount of ethanol was reduced to
10% in a solvent of acetonitrile, only a trace of 10a was
observed after refluxing for 44 h. The major product was the
xanthene-1,4-dione 12 (37%), and a significant amount
(44%) of starting material was recovered. In related studies
ethanolic solutions of the quinones 9b (R1ZOMe, R2Z
n-Bu, R3ZMe) and 9c (R1Zn-Bu, R2ZOMe, R3ZMe)
gave the corresponding 10b (R1ZOMe, R2Zn-Bu, R4ZEt)
and 10c (R1Zn-Bu, R2ZOMe, R4ZEt) in respective yields
of 63 and 67% along with 5 and 7% of the dimers 11b (R1Z
OMe, R2Zn-Bu) and 11c (R1Zn-Bu, R2ZOMe) after
reaction times of 6 h for 9b and 45 min for 9c at reflux
temperature. Quinone 9d (R1ZR2ZOMe, R3ZPh) also
gave 10a in 70% yield. However, the bulkier triphenylsilyl
group significantly retarded the reaction rate; 32 h in
refluxing ethanol was required as compared to 45 min for
the trimethyl analogs, 9a,c and 6 h for 9b.
converted to 18 in 27% yield along with quinone 10a in 30%
yield.
Quinone 19 was found to be stable in dry refluxing THF
after 7 h. However, addition of a catalytic amount
(10 mol%) of thiophenol resulted in the formation of the
symmetrical dimer 20 (29%) along with recovered starting
material after an additional 4 h at reflux. Similar behavior
was observed with the mercaptoethanol-substitued quinone
21. Heating solutions of this quinone in refluxing THF for
5 h or toluene for 8 h failed to induce any reaction.
However, heating a dilute aqueous acetonitrile solution of
21 for 3 h induced the formation of symmetrical dimer 22
and the annelated quinone 23 in respective yields of 30 and
40%.
The reaction rates of a variety of quinones with ethanol were
studied to determine the influence of ring substitution. The
reactions of 9a as well as the regioisomeric n-butyl-
substituted quinones 9b, and 9c were measured in ethanol-
d6 at 708 by 1H NMR. The disappearance of the methylene
group resonance as a function of time was monitored using
the methyl group resonance of p-xylene as an internal
standard. Due to the limited solubility of triphenylsilyl-
substituted quinone 9d in ethanol, the reaction rate of this
quinone was followed by HPLC. In all cases, the reactions
exhibited clean pseudo first-order kinetic behavior. The half
lives of 9a,b,c,d at 70 8C were calculated to be, respectively,
21 min, 85 min, 28 min and 15 h. The reaction of the
bromoquinone 14 with ethanol was much too fast to be
measured accurately at 70 8C. Therefore, the rate of reaction
was studied by 1H NMR at 30 8C in ethanol-d6, revealing a
half life of 13 min.
The steric bulk of the alcohol also influences the reaction
course. For example, when solutions of 9a in iso-propanol
and tert-butanol were refluxed, the reaction times increased
to 9 and 44 h, respectively. Also, the yields of the
corresponding
alkoxymethyl-substituted
quinones
decreased and the yield of the symmetrical dimer increased.
In iso-propanol the quinone 10d (R1ZR2ZOMe, R4Zi-Pr)
and the dimer 11a were obtained in 65 and 10%,
respectively, as compared to yields of 10e (R1ZR2Z
OMe, R4Zt-Bu) (45%) and 11a (16%) in tert-butanol.
In a related study a solution of 9a in 5% aqueous acetonitrile
was refluxed for 8 h followed by subsequent oxidation
(Ag2O). Here, the quinone 10f (R1ZR2ZOMe, R4ZH)
(12%), the symmetrical dimer 11a (46%) and the xanthene-
1,4-dione 12 (22%) were realized. Interestingly, the amount
of water had a significant effect on the product distribution.
For example, when 10% aqueous acetonitrile was
employed, the dimer 11a and quinone 10f were realized in
respective yields of 67 and 18%, and the xanthene-1,4-dione
12 was detected in only trace amounts.
The data outlined above are consistent with the mechanism
provided in Scheme 2. In this regard, the following points
are of particular note:
1. The rate-limiting step is nucleophilic attack on the silyl
group of quinone 4 to produce the enolate anion 5. The
difference in the reaction rates of 9a and 9d is
particularly revealing in this regard. The data show the
less bulky quinone 9a to react approximately 43 times
faster than its more hindered analog 9d at 70 8C. The
difference in rate between the other quinones is also
noteworthy. For example, the half-life of the bromoqui-
none 14 is 13 min at 30 8C while that of 9a is 21 min at
70 8C. Here again, the data suggest enolate anion
formation in the rate-limiting step, that is, the electro-
negative bromine adds stability to the enolate and thus
increases the reaction rate. The observed rate differences
between the other quinones are less remarkable, but even
here the data suggest the importance of enolate stability.
Note, for example, the rate difference between the
regioisomeric quinones, that is, 9b/9cZ1:3. This would
be consistent with anion stabilization in 5. Thus 9b
(R1ZOMe) would result in a vinylogous ester enolate
while 9c (R1Zn-Bu) would give a more stable keto
enolate.10
Further data were obtained when a solution of 9a in glacial
acetic acid containing 6 equiv of sodium acetate was heated
to reflux for 0.5 h. The major product detected was the
quinone 10g (R1ZR2ZOMe, R4ZAc) (79%) along with
!2% of dimer 11a. When the amount of sodium acetate
was reduced to 0.1 equiv the observed products were the
quinone 10g (30%) and recovered starting material. In
acetic acid alone quinone 10g was realized in 54% along
with 10% recovered starting material. Dimer 11a was not
detected from the reactions containing 0.1% NaOAc or in
pure acetic acid.
Additional examples are presented in Scheme 4. Treatment
of 9a with 10% aqueous acetonitrile in the presence of
excess n-butyl vinyl ether gave the chromanol 13 in 72%
yield. Quinone 14 was found to readily react with ethanol.
After only 10 min at reflux followed by an oxidative (Ag2O)
workup, quinone 15 along with dimer 16 were realized in 55
and 10%, respectively. Under analogous conditions 17 was
2. Unambiguous data for the silyloxy quinone methide 6 as
opposed to the protio analog was not obtained. However,
the silyl analog is favored on the basis of the results
obtained when 9a was treated with acetic acid or acetic

278
J. E. Ezcurra et al. / Tetrahedron 61 (2005) 275–286
Scheme 4.
acid/sodium acetate. Under these acidic conditions no
dimers 11 may be formed by Michael addition of enolate
5 to o-quinone methide 6.
simple protio desilylated product (e.g., 2,3-dimethoxy-5-
methyl-1,4-benzoquinone) was detected. These data are
in agreement with the mechanistic paradigm outlined in
Scheme 2, that is, O-silylation of the enolate 5 to give
the quinone methide 6 is presumably favored over
O-protonation. This intermediate then functions as the
key precursor to the observed reaction products.
Quinones 9a,b,c,d, 14, 17, 19 and 21, needed for the study
reported herein, find their synthetic genesis in the previously
reported thermal rearrangement of 4-alkynyl and
4-alkenylcyclobutenones (Scheme 5).13 For example, 3-n-
butyl-4-methoxycyclobuten-1,2-dione (24) was converted
to the corresponding adducts 25 and 26 (R1Zn-Bu, RZMe)
upon treatment with the appropriate alkynyl or vinyl lithium
reagent to the more reactive carbonyl group. These then
gave the respective regioisomeric quinone 9b (92%) and 9c
(75%) upon thermolysis (p-xylene,138 8C). In a similar
fashion 26 (R1ZOMe, RZPh) gave 9d (92%) and 27 gave
17 (95%). Treatment of 17 with HBr in THF followed by
oxidation (Ag2O) of the resulting hydroquinone gave 14
(50%). Quinone 21 (70%) was obtained from 9a upon
treatment with mercaptoethanol followed by an oxidative
work up. Quinone 19 (53%) was obtained analogously using
thiophenol.
3. The above reactions are in agreement with an o-quinone
methide precursor. Selected examples are noted below.
Quinones of general structure 10 are envisaged to arise
via Michael additions of ROH to the enone of the
o-quinone methide followed by oxidation of the resulting
silylated hydroquinone.4g,11 As the concentration of
ROH decreases (see, for example, entry b in Scheme 3)
the o-quinone methide is competitively trapped by the
starting quinone in a Diels–Alder reaction to give the
xanthene-1,4-dione 12. Analogously, the o-quinone
methide can be intercepted to give 13 when generated
in the presence of excess n-butylvinyl ether. The dimers
of general structure 11 may arise via an initial Diels–
Alder dimerization of the quinone methides, a known
reaction pathway for such intermediates.12 Alternatively,
The facility of o-quinone methide formation from
(trimethylsilyl)methyl-1,4-benzoquinones under mild and

J. E. Ezcurra et al. / Tetrahedron 61 (2005) 275–286
279
Scheme 5.
neutral conditions can be used as a paradigm to guide the
design of potentially bioactive compounds. For example,
quinones bearing an intercalating group as well as the
(trimethylsilyl)methyl group might effectively cleave DNA.
To this end, quinone 31 was prepared as outlined in
Scheme 6. Addition of 9-thioanthracene to 3-methoxy-4-
alkenylcyclobutene-1,2-dione gives 29 in 60% yield.14 This
was converted to 30 upon addition of 1-lithio-3-trimethyl-
silylpropyne, thermolysis of which (acetonitrile, reflux)
gave the desired quinone 31 in 64% yield.
3. Conclusions
In conclusion, the most significant aspects of this work
include the following: (1) trialkylsilyl (or triarylsilyl)-
methyl-1,4-benzoquinones
4 function as excellent
precursors to o-quinone methide intermediates 6; (2) the
quinone methides can be generated under mild and neutral
conditions; (3) the mechanism involves nucleophilic attack
at the silyl group with displacement of the corresponding
vinylogous enolate anion; (4) anion stabilizing groups on
the quinone nucleus at those positions that enhance anion
stabilization facilitate the rate of the reaction; (5) a general
method for the synthesis of trialkylsilyl (or triarylsilyl)-
methyl-1,4-benzoquinones from substituted cyclobuten-1,2-
diones is presented; (6) quinone 31, bearing an
intercalating group as well as well as a (trimethylsilyl)-
methyl substituent, was prepared and observed to cleave
supercoiled DNA.
When quinone 31 was incubated with supercoiled DNA
at 51 8C for 21 h cleavage to the relaxed circular form was
observed as evidenced by agarose gel electrophoresis
with ethidium bromide stain. Moreover, it was observed
that added ethidium bromide inhibits cleavage of
the supercoiled DNA by effectively competing for the
intercalation sites.

280
J. E. Ezcurra et al. / Tetrahedron 61 (2005) 275–286
Scheme 6.
4. Experimental
(350 mg, 2.46 mmol) in 25 mL of THF was added via
cannula over 5 min. The mixture was stirred for 10 min and
then quenched with 5% NH4Cl (20 mL) and allowed to
warm to room temperature. Ether (100 mL) was added and
the aqueous layer was extracted twice with ether (2!
20 mL). The combined organic layers were washed with
brine and dried over anhyd. MgSO4. Evaporation of the
solvent followed by flash chromatography on silica gel
(hexanes/ethyl acetate, 3:1) afforded 469 mg (75%) of the
title compound as a cream colored solid: mp 75–76 8C; IR
4.1. General
All air or water sensitive reactions were carried out under a
slight pressure of nitrogen or argon. Dry solvents were
distilled from calcium hydride. THF and ethyl ether were
further distilled from sodium (benzophenone indicator).
Unless specified as dry, solvents were unpurified reagent
grade. Glassware was flame-dried under a stream of
nitrogen or argon, where appropriate. In cases where
products were isolated by ‘aqueous work-up’, the procedure
was to quench the reaction by addition of 5% NH4Cl to the
reaction mixture followed by dilution with ethyl ether. The
combined organic layers were washed with brine and dried
with MgSO4 before concentration in vacuo to yield the
crude products. Flash column chromatography was per-
formed using E.Merck silica gel (230–400 mesh) or Fisher
Scientific florisil (100–200 mesh). Radial chromatography
was performed on a model 7924T chromatotron from
Harrison Research, Palo Alto, CA. Melting points were
taken on a Buchi 50 melting point apparatus and are not
corrected. NMR spectra were recorded on a Bruker 250 or
300 MHz or General Electric QE 300, QE 500 or Omega
500 MHz NMR spectrometers. IR spectra were obtained on
a Perkin Elmer 1620 spectrophotometer (single beam). Low
resolution mass spectra were obtained from a Finnigan 400
spectrometer; high resolution mass spectra were obtained on
a VG Analytic 7070E spectrometer. Elemental analyses
were performed by Robertson Laboratories, Inc., Madison,
NJ.
1
(CDCl3) 3580, 1785 cmK1; H NMR (300 MHz, CDCl3) d
4.18 (s, 3H), 3.96 (s, 3H), 2.79 (br s, 1H), 1.56 (s, 2H), 0.11
(s, 9H); 13C NMR (500 MHz, CDCl3) d 181.6, 165.2, 135.2,
89.1, 78.8, 73.2, 59.8, 58.5, 7.4, K2.0; LRMS m/e (rel.
intens.) EI 239 (4), 73 (100); CI 255 (100), 237 (19), 223
(18); HRMS CI m/e calcd for C12H18O4Si: (MHC)
255.1052, found: 255.1040.
4.1.2. 2,3-Dimethoxy-4-hydroxy-3-(trimethylsilylpro-
pen-2-yl)cyclobut-2-en-1-one, 26, R1ZOCH3, RZ
CH3—representative procedure for alkenyllithium
addition. A solution of 2-bromoallyltrimethylsilane
(1.20 g, 6.21 mmol) in 10 mL of dry THF was introduced
dropwise to a solution of t-butyllithium (8.0 mL of a 1.5 M
solution in hexanes, 12.0 mmol) in 100 mL of THF at
K78 8C. After stirring for 30 min, a solution of dimethyl
squarate (0.80 g, 5.63 mmol) in 50 mL of THF at K78 8C
was added via cannula over 5 min. The resulting solution
was stirred for 10 min and then quenched with 5% NH4Cl
and allowed to warm to ambient temperature. Ether
(100 mL) was added and the aqueous layer was separated
and back-extracted with ether (2!20 mL). The combined
organic layers were washed with brine and dried with anhy.
MgSO4. Evaporation of the solvent followed by flash
column chromatography (hexanes/ethyl acetate, 3:1)
afforded 1.03 g (72%) of the title compound as a light
yellow oil. IR (CDCl3) 3580, 1775 cmK1; 1H NMR (CDCl3)
d 5.20 (s, 1H), 4.91 (s, 1H), 4.10 (s, 3H), 3.96 (s, 3H), 2.71
(s, 1H), 1.64 (d, JZ0.6 Hz, 2H), 0.05 (s, 9H); LRMS m/e
4.1.1. 2,3-Dimethoxy-4-hydroxy-4-(3-trimethylsilylpro-
pyn-1-yl)cyclobut-2-en-1-one 25, R1ZOCH3—represen-
tative procedure for alkynyllithium addition.
n-Butyllithium (1.8 mL of a 1.6 M solution in hexane,
2.88 mmol) was added to a solution of 3-trimethylsilylpro-
pyne (331 mg, 2.96 mmol) in 50 mL of dry THF at K78 8C.
After 10 min, a pre-cooled solution of dimethyl squarate

J. E. Ezcurra et al. / Tetrahedron 61 (2005) 275–286
281
(EI, rel. intens.) 256 (MC, 25), 241 (22), 225 (32), 73 (100).
Anal. Calcd for C14H20O4Si: 56.22% C; 7.86% H, found:
55.97% C, 7.94% H.
(100); HRMS (EI) m/e calcd for C15H26O3Si: (MC)
282.1651, found: 282.1641.
4.1.6. 2-Bromo-3-triphenylsilyl-1-propene. Triphenylsi-
lyllithium was prepared by mixing triphenylsilyl chloride
(4.72 g, 16 mmol) with thinly sliced lithium metal wire
(0.54 g, 80 mmol) in 20 mL of dry THF for 22 h at ambient
temperature. The resulting green solution was cooled to 0 8C
and then added to freshly dried CuI (1.52 g, 8 mmol). The
mixture was stirred at 0 8C for 30 min and then cooled to
K78 8C. A pre-cooled solution of 2,3-dibromopropene
(6.6 mmol) in 5 mL of THF was added to the mixture.
The resulting mixture was stirred at K78 8C for 30 min and
then allowed to warm to ambient temperature. The reaction
mixture was poured into a mixture of 1:1 pentane/5%
NH4Cl (60 mL) and stirred vigorously. The mixture was
filtered through glass wool and the layers were separated.
The aqueous layer was back-extracted with ether. The
combined organic layers were dried over MgSO4 and
concentrated in vacuo. The resulting tan solid was purified
by flash column chromatography (silica gel, hexanes/ethyl
acetate, 12:1) followed by crystallization from boiling
hexanes to afford 1.98 g (79%) of the title compound as
white crystals: mp 91.5–92.5 8C; IR (CDCl3) 3052, 3014,
4.1.3. 2,3-Dimethoxy-4-(3-trimethylsilyl-1-propynyl)-4-
trimethylsiloxycyclobenone, 27. 1-Lithio-3-trimethylsilyl-
propyne was generated and added to dimethyl squarate
(150 mg, 1 mmol) as described for 25. The resulting
solution was stirred for ten min at K78 8C and then
quenched by addition of trimethylsilylchloride (0.18 mL,
1.4 mmol). The solution was stirred at K78 8C for an
additional ten min and then concentrated in vacuo. The
residue was diluted with ether and quickly filtered through a
plug of fluorisil. Concentration in vacuo gave 324 mg (95%)
of the title compound as a clear oil. IR (CDCl3) 1780 cmK1
;
1H NMR (300 MHz, CDCl3) d 4.15 (s, 3H), 3.94 (s, 3H),
1.56 (s, 2H), 0.22 (s, 9H), 0.11 (s, 9H); 13C NMR (500 MHz,
CDCl3) d 181.7, 166.2, 134.5, 88.5, 79.5, 74.3, 59.6, 58.4,
7.4, 1.2, K1.9; HRMS m/e (CI) calcd for C15H27O4Si2:
327.1428, found: 327.1427.
4.1.4. 2-n-Butyl-4-hydroxy-3-methoxy-4-(3-trimethylsi-
lyl-1-propynyl)cyclobutenone, 25 R1Zn-butyl. The
representative procedure for 25 was followed using 3-n-
butyl-4-methoxycyclobut-3-ene-1,2-dione, 24, R1Zn-
butyl, as the starting material. Purification by flash column
chromatography (hexanes/ethyl acetate, 3:1) gave 534 mg
(54%) of the product as a yellow solid: mp 42–43 8C; IR
(CDCl3) 3580, 2230, 1765 cmK1; 1H NMR (CDCl3) d 4.21
(s, 3H), 3.55 (bs, 1H), 2.04 (t, JZ7.0 Hz, 2H), 1.55 (s, 2H),
1.49 (pentet, JZ7.1 Hz, 2H), 1.30 (sextet, JZ7.1 Hz, 2H),
0.87 (t, JZ7.1 Hz, 3H), 0.09 (s, 9H); 13C NMR (CDCl3) d
187.9, 180.7, 129.3, 89.9, 82.9, 73.5, 59.4, 28.9, 22.4, 21.5,
13.7, 7.5, K2.0 (3C); LRMS m/e (EI, rel. intens.) 280 (MC,
1), 265 (17), 73 (100). CI 281 (MHC, 100); HRMS (CI) m/e
calcd for C15H24O3Si: (MHC) 281.1573, found: 281.1553.
1
1618, 1487, 1428, 1193, 1111, 872, 700 cmK1; H NMR
(300 MHz, CDCl3) d 7.70–7.50 (m, 6H), 7.50–7.26 (m, 9H),
5.34 (d, JZ1.6 Hz, 1H), 5.30 (d, JZ1.8 Hz, 1H), 2.98 (d,
JZ0.8 Hz, 2H); 13C NMR (500 MHz, CDCl3) d 135.9,
133.5, 129.8, 129.2, 127.8, 117.4, 30.0; HRMS m/e (CI)
calcd for C21H19Si: 299.1256, found: 299.1230; 341 (4), 340
(15), 339 (4), 338 (10), 302 (2), 301 (7), 263 (20), 261 (20),
260 (24), 259 (100).
4.1.7. 4-Hydroxy-2,3-dimethoxy-4-(1-((triphenylsilyl-
methyl)ethenyl)-2-cyclobutenone, 26, R1ZOMe, RZ
Ph. To a cooled (K78 8C) solution of t-butyllithium
(3.7 mmol) in 50 mL of dry THF was added a pre-cooled
(K78 8C) solution of 2-bromo-3-triphenylsilylprop-1-ene
(644 mg, 1.7 mmol) in 40 mL of dry THF via cannula. The
resulting solution was stirred for 15 min at K78 8C. A pre-
cooled solution (K78 8C) of dimethyl squarate (200 mg,
1.4 mmol) in 50 mL of dry THF was added via cannula. The
reaction mixture was stirred for 30 min at K78 8C and then
worked up. Purification by flash column chromatography
(silica gel, hexanes/ethyl acetate, 1:1) provided the title
compound as a white solid (365 mg, 59%): mp 112–113 8C;
IR (CDCl3) 3580, 1773 cmK1; 1H NMR (300 MHz, CDCl3)
d 2.3 (s, 1H), 2.51 (d, JZ15 Hz, 1H), 2.6 (d, JZ15 Hz 1H),
3.86 (s, 3H), 3.91 (s, 3H), 4.9 (s, 1H), 5.2 (s, 1H), 7.36–7.43
(m, 9H), 7.57–7.58 (m, 6H); 13C NMR (500 MHz, CDCl3) d
17.7, 58.5, 60.1, 89.1, 114.9, 127.95, 129.7, 134.4, 134.5,
136.0, 141.8, 165.8, 184.3; HRMS m/e (EI, rel. intens.)
calcd for C27H26O4Si: 442.1600, found: 442.1633; 442
(1.4), 410 (4.4), 411 (1.3), 364 (40.6), 365 (8.8), 349 (19),
350 (4.3), 259 (100), 260 (20.7), 261 (5.1), 180 (12.9), 181
(33.5), 182 (6.5), 105 (30.8).
4.1.5. 2-n-Butyl-4-hydroxy-3-methoxy-4-(3-trimethylsi-
lylpropenyl)-cyclobutenone, 26 R1Zn-butyl. The repre-
sentative procedure for 26 was followed using 4-n-butyl-3-
methoxycyclobutenedione 24 (RZn-butyl) and 3-trimethyl-
silylpropyne as starting materials. Flash chromatography
(hexanes/ethyl acetate, 4:1) gave 550 mg (53%) as a light
yellow oil. IR (CDCl3) 3580, 3460, 1760; 1H NMR (CDCl3)
d 5.15 (d, JZ0.5 Hz, 1H), 4.89 (s, 1H), 4.04 (s, 3H), 2.07
(m, 2H), 1.60 (s, 2H), 1.47 (pentet, JZ7.4 Hz, 2H), 1.30
(sextet, JZ7.4 Hz, 2H), 0.87 (t, JZ7.4 Hz, 3H), 0.02 (s,
9H); 13C NMR (CDCl3) d 191.6, 182.3, 143.6, 129.0, 111.2,
94.0, 59.3, 29.3, 22.5, 21.6, 21.5, 13.6, K1.0 (3C); LRMS
m/e (EI, rel. intens.) 282 (MC, 0.6), 208 (1.5), 73 (100);
HRMS (EI) m/e calcd for C15H26O3Si: (MC) 282.1651,
found: 282.1640.
Also isolated in 10% yield (101 mg) was the regioisomer as
a yellow oil. IR (CDCl3) 3590, 2960, 1765; 1H NMR
(CDCl3) d 5.07 (s, 1H), 4.88 (d, JZ0.9 Hz, 1H), 4.00 (s,
3H), 2.32–2.45 (m, 3H overlapping methylene and hydroxy
protons), 1.64 (quintet, JZ7.1 Hz, 2H), 1.60 (d, JZ1.0 Hz,
2H), 1.38 (sextet, JZ7.4 Hz, 2H), 0.92 (t, JZ7.3 Hz, 3H),
0.04 (s, 9H); 13C (CDCl3) d 188.7, 157.5, 154.8, 144.8,
111.1, 91.5, 58.1, 28.8, 25.1, 23.0, 22.1, 13.7, K1.0 (3C);
LRMS m/e (EI, rel. intens.) 282 (MC, 0.05), 239 (0.5), 73
4.1.8. 2,3-Dimethoxy-5-((trimethylsilylmethyl)-1,4-ben-
zoquinone, 9a. Representative procedure for the
rearrangement of 4-alkenyl substituted cyclobutenones
to trimethylsilylmethyl-substituted benzoquinones.
Method A. A solution of 26 (R1ZOMe, RZCH3), (1.01 g,
3.94 mmol), in 100 mL of p-xylene was heated at reflux for

282
J. E. Ezcurra et al. / Tetrahedron 61 (2005) 275–286
15 min. After cooling to ambient temperature, Ag2O (2.0 g,
7.94 mmol) was added and the mixture was stirred for
15 min. Filtration and evaporation of the solvent gave the
crude product. Purification by flash column chromatography
(hexanes/ethyl acetate, 5:1) yielded 0.90 g (89%) of the title
280 (9), 265 (22), 209 (25), 73 (100); Anal. Calcd for
C15H24O3Si: C, 64.24; H, 8.63, found: C, 64.24; H, 8.74.
4.1.12. 3-n-Butyl-2-methoxy-6-((trimethylsilyl)methyl)-
1,4-benzoquinone, 9b. This quinone was prepared by
thermolysis of 26 (R1Zn-butyl, RZCH3) according to
method A. Purification by flash column chromatography
(hexanes/ethyl acetate, 95:5) provided 366 mg (92%) of the
title compound as a golden yellow oil. IR (CDCl3) 2980,
compound as a deep red oil. IR (CDCl3) 2690, 1660 cmK1
;
1H NMR (CDCl3) d 6.23 (t, JZ0.8 Hz, 1H), 4.04 (s, 3H),
3.94 (s, 3H), 1.97 (d, JZ0.8 Hz, 2H), 0.02 (s, 9H); LRMS
m/e (EI, rel. intens.) 254 (MC, 12), 239 (16), 226 (33), 211
(19), 195 (10), 73 (100). Anal. Calcd for C12H18O4Si: C,
56.67; H, 7.13, found: C, 56.44; H, 6.99.
1
1670, 1650 cmK1; H NMR (CDCl3) d 6.30 (t, JZ1.0 Hz,
2H), 3.92 (s, 3H), 2.40 (t, JZ7.1 Hz, 2H), 1.95 (d, JZ
1.0 Hz, 2H), 1.34–1.38 (m, 4H), 0.90 (t, JZ7.1 Hz, 3H),
0.02 (s, 9H); LRMS m/e (CI, rel. intens.) 281 (MHC, 100),
267 (4). Anal. Calcd for C15H24O3Si: C, 64.24; H, 8.63,
found: C, 64.24; H, 8.96.
Method B. Heating a solution of 4-alkynyl substituted
cyclobutenone, 25 (R1ZOMe), in p-xylene at reflux for
15 min followed by evaporation of the solvent and
purification by flash column chromatography provided the
title compound directly without the need for Ag2O
oxidation. The spectral properties were identical to the
product derived from 26.
4.1.13. 5,6-Dimethoxy-2-thiophenyl-3-((trimethylsilyl)-
methyl)-1,4-benzoquinone, 19. A mixture of quinone 9a
(100 mg, 0.39 mmol), thiophenol (83.0 mg, 0.79 mmol) in
5 mL of THF was stirred at room temperature for 16 h.
Evaporation of the solvent and flash column chromato-
graphy (hexanes/ethyl acetate, 3:1) gave the intermediate
hydroquinone, which was oxidized with Ag2O (218 mg,
0.867 mmol) in 10 mL of benzene. Filtration of the silver
salts, evaporation of the solvent and purification by flash
column chromatography (hexanes/ethyl acetate, 3:1) gave
75.0 mg (53%) of the product as a red solid: mp 61–62 8C;
4.1.9. 2,3-Dimethoxy-5-trimethylsilyl-6-((trimethylsilyl)-
methyl)-1,4-benzoquinone, 17. A solution of cyclobute-
none 27 (297 mg, 0.91 mmol) and 60 mL of dry p-xylene
was heated at reflux for 1 h. Concentration in vacuo
followed by flash column chromatography on silica gel
(hexanes/ethyl acetate, 10:1) provided 190 mg (65%) of the
product as an orange oil. IR (CDCl3) 1641, 1564 cmK1; 1H
NMR (300 MHz, CDCl3) d 0.03 (s, 9H), 0.28 (s, 9H), 2.27
(s, 2H), 3.90 (s, 3H), 4.02 (s, 3H); 13C NMR (500 MHz,
CDCl3) D 188.15, 184.38, 156.17, 145.24, 143.19, 138.73,
60.95, 60.87, 21.19, 1.95, K0.23; HRMS (EI, rel. intens.)
m/e calcd for C15H27O4Si2; 327.1475, found: 327.1421; 326
(0.8), 311 (7.8), 298 (22), 281 (4), 268 (3), 253 (11), 147 (8),
135 (11), 133 (12), 89 (12), 73 (100), 59 (13).
1
IR (CDCl3) 1665, 1635 cmK1; H NMR (CDCl3) d 7.27–
7.20 (m, 5H), 3.99 (s, 3H), 3.94 (s, 3H), 2.52 (s, 2H), 0.08 (s,
9H); LRMS m/e (CI, rel. intens.) 363 (MHC, 100); Anal.
Calcd for C18H20O4SSi: C, 59.64; H, 6.12, found: C, 59.77;
H, 5.94.
4.1.14. 5,6-Dimethoxy-2-(2-hydroxyethyl-1-thio)-3-tri-
methylsilylmethyl-1,4-benzoquinone, 21. A mixture of
9a (100 mg, 0.39 mmol), mercaptoethanol (34.0 mg,
0.44 mmol) and 5 mL of absolute ethanol was stirred at
room temperature for 15 min. Evaporation of the solvent
followed by flash column chromatography (hexanes/ethyl
acetate, 3:1) gave 110 mg of the intermediate hydroquinone,
which was oxidized with Ag2O (175 mg) in 10 mL of
benzene at ambient temperature for 15 min. Purification of
the quinone by flash column chromatography (hexanes/
ethyl acetate, 3:2) furnished 92 mg (70%) of the product as a
deep red oil in O96% purity (1H NMR). IR (CDCl3) 3500,
4.1.10. 2,3-Dimethoxy-6-((triphenylsilyl)methyl)-1,4-
benzoquinone, 9d. A solution of cyclobutenone 6 (R1Z
OMe, RZPh; 25 mg, 0.05 mmol)) in 1 mL of p-xylene was
heated at reflux for 30 min. The solution was cooled to room
temperature and treated with Ag2O (350 mg, 1.5 mmol).
After 15 min, the solution was filtered. Concentration
followed by flash column chromatography (hexanes/ethyl
acetate, 4:1) yielded 20.3 mg (92%) of the product as a
yellow solid: mp 122.5–123 8C; IR (CDCl3) 1655 cmK1; 1H
NMR (300 MHz, CDCl3) d 2.8 (s, 2H), 3.6 (s, 3H), 3.96
(s, 3H), 6.15 (s, 1H), 7.37–7.43 (m, 9H), 7.53–7.55 (m, 6H);
13C NMR (500 MHz, CDCl3) d 183.5, 183.3, 146.9, 144.8,
144.2, 135.8, 132.9, 129.9, 128.5, 128.0, 60.9, 60.9, 16.7;
LRMS (EI, rel. intens.) m/e 440 (4.98), 425 (9.9), 363 (7.1),
347 (3.9), 259 (100), 260 (22.4), 213 (18.1), 181 (36.9), 180
(13.3), 155 (14); Analysis calcd for C27H24O4Si: C, 73.61;
H, 5.49, found: C, 73.53; H, 5.42.
1
2960, 1670–1640 cmK1; H NMR (CDCl3) d 4.02 (s, 3H),
3.96 (s, 3H), 3.74 (q, JZ5.9 Hz, 2H), 3.13 (t, JZ6.0 Hz,
2H), 2.45 (s, 2H), 2.28 (t, JZ6.1 Hz, 1H), 0.05 (s, 9H); 13C
NMR (CDCl3) d 181.7, 180.2, 150.3, 145.2, 144.0, 135.3,
61.6, 61.2, 61.0, 37.3, 22.3, K0.6 (3C); HRMS (EI, rel.
intens.) m/e calcd for C14H22O5SSi: 330.0957, found:
330.0960; 330 (1), 149 (40), 73 (100); LRMS (CI, rel.
intens.) 331 (MHC, 100), 287 (22).
4.1.11. 3-n-Butyl-2-methoxy-5-((trimethylsilyl)methyl)-
1,4-benzoquinone, 9c. This quinone was prepared by
thermolysis of 25 (R1Zn-butyl) according to method B.
Purification by flash column chromatography (hexanes/
ethyl acetate, 95:5) gave 390 mg (75%) of the product as a
golden yellow oil. IR (CDCl3) 1650, 1595 cmK1; 1H NMR
(CDCl3) d 6.22 (t, JZ0.9 Hz, 1H), 4.01 (s, 1H), 2.43 (t, JZ
7.1 Hz, 2H), 1.98 (d, JZ0.9 Hz, 2H), 1.35–1.32 (m, 4H),
0.91 (t, JZ7.0 Hz), 0.01 (s, 9H); LRMS m/e (EI, rel. intens.)
4.1.15. Heterocyclic quinone 23 and symmetrical dimer
22. Quinone 21 (80 mg, 0.24 mmol) was heated at reflux in
200 mL of acetonitrile/water (197:3) for 3 h. The solvent
was removed and the residue oxidized with Ag2O (183 mg,
0.73 mmol) in 10 mL of benzene/acetonitrile (9:1) at
ambient temperature for 30 min. After filtration and
removal of the solvent, purification by flash chromatog-
raphy (chloroform/methanol, 97:3) gave 24.7 mg (40%) of
23 as a red solid: mp 108–109 8C; IR (CDCl3) 2950, 2860,

J. E. Ezcurra et al. / Tetrahedron 61 (2005) 275–286
283
1
1650 (br), 1580 cmK1; H NMR (CDCl3) d 4.70 (s, 2H),
4.03 (t, JZ5.5 Hz, 2H), 4.02 (s, 3H), 3.94 (s, 3H), 3.18
(t, JZ5.6 Hz, 3H); 13C NMR (CDCl3) d 181.1, 181.0, 148.1,
145.2, 143.6, 135.8, 71.2, 64.2, 61.4, 61.2, 33.5; MS (EI, rel.
intens.) m/e 256 (MC, 18), 213 (30), 185 (27), 129 (37), 85
(66), 69 (100), 57 (87); Anal. Calcd for C11H12O5S: C,
51.55; H, 4.72, found: C, 51.41; H, 4.83. Further elution
gave dimer 22 which was re-purified by flash column
chromatography (chloroform/methanol, 20:1) to give
18.8 mg (30%) of 22 as an orange solid: mp 114–116 8C;
4.2. General procedure for the reaction of
((trimethylsilyl)methyl)-1,4-benzoquinones with
alcohols
A solution of the benzoquinone in 10 mL of the alcohol was
heated at reflux for the appropriate time. The alcohol was
removed in vacuo and the intermediate hydroquinone was
re-dissolved in benzene and oxidized by the addition of
20 equiv of Ag2O at room temperature for 15 min. Filtration
of the solution and evaporation of the solvent gave the crude
product which was purified by flash column
chromatography.
IR (CDCl3) 3540, 1660, 1575 cmK1; H NMR (CDCl3) d
1
3.99 (s, 6H), 3.98 (s, 6H), 3.78 (m, 4H), 3.22 (t, JZ5.4 Hz,
4H), 2.96 (s, 4H), 2.60 (br s, 2H); HRMS (EI, rel. intens.)
m/e calcd for C22H26O10S2: 514.0967, found: 514.0947; 514
(MC, 5), 257 (7), 227 (18), 215 (21), 60 (100).
4.2.1. 2,3-Dimethoxy-5-(ethoxymethyl)-1,4-benzoqui-
none, 10a. Quinone 9a was heated at reflux in absolute
ethanol for 45 min. After oxidation and purification by flash
column chromatography (silica gel, hexanes/ethyl acetate,
3:1), the title compound was isolated in 82% yield as an
orange oil which solidified upon cooling: mp 38–39 8C; IR
(CDCl3) 1660, 1605 cmK1; 1H NMR (CDCl3) d 6.63 (t, JZ
2.2 Hz, 1H), 4.32 (d, JZ2.2 Hz, 2H), 4.02 (s, 3H), 3.98
(s, 3H), 3.58 (q, JZ7.0 Hz, 2H), 1.23 (t, JZ7.0 Hz, 3H);
LRMS (EI, rel. intens.) m/e 226 (95), 197 (69), 180 (100),
164 (49), 150 (41), 67 (60); Anal. Calcd for C11H14O5: C,
58.40; H, 6.24, found: C, 58.49; H, 6.32.
4.1.16. Reaction of quinone 9a with n-butylvinyl ether.
Chromanol, 13. A mixture of quinone 9a (100 mg,
0.39 mmol), n-butylvinyl ether (800 mg, 8.0 mmol) and
10 mL of acetonitrile/water (9:1) was heated at reflux for
2.5 h. The mixture was concentrated in vacuo and 25 mL of
ether was added. The layers were separated and the aqueous
layer extracted twice with ether (2!10 mL). The combined
organic layers were washed twice with brine (2!5 mL) and
dried over MgSO4. Evaporation of the solvent and
purification by flash column chromatography (hexanes/
ethyl acetate, 3:1) gave 80 mg (72%) of 13 as a yellow oil.
Further elution with hexanes/ethyl acetate, 2:1 gave 5%
of the symmetrical dimer 11a as an orange solid: mp
IR (CDCl3) 3550, 2985, 1620–1580 cmK1 1H NMR
;
133–134 8C; IR (CDCl3) 1660, 1605 cmK1 1H NMR
;
(CDCl3) d 5.46 (s, 1H), 5.26 (t, JZ2.7 Hz, 1H), 3.91
(s, 3H), 3.90 (s, 3H), 3.84 (dt, JZ9.5, 6.7 Hz, 1H), 3.59
(dt, JZ9.6, 6.6 Hz, 1H), 2.91–2.84 (m, 1H), 2.54–2.49
(m, 1H), 2.02–1.97 (m, 1H); 1.92–1.85 (m, 1H), 1.54
(quintet, JZ7.0 Hz, 2H), 1.30 (sextet, JZ7.3 Hz, 3H), 0.87
(t, JZ7.3 Hz, 3H); 13C NMR (CDCl3) d 142.2, 141.2, 138.7,
138.5, 118.6, 108.9, 96.7, 68.0, 61.2, 60.8, 31.6, 26.4, 20.3,
19.2, 13.7; LRMS (EI, rel. intens.) m/e 282 (MC, 21), 182
(100); Anal. Calcd for C15H22O5: C, 63.81; H, 7.85, found:
C, 63.85; H, 7.80.
(CDCl3) d 6.39 (t, JZ0.8 Hz, 1H), 4.06 (s, 3H), 4.00
(s, 3H), 2.63 (d, JZ0.8 Hz, 2H); LRMS (EI, rel. intens.) m/e
362 (MC, 8), 347 (13), 181 (14), 67 (100); Anal. Calcd for
C18H18O8: C, 59.67; H, 5.01: found: C, 59.38; H, 4.89.
4.2.2. 3-n-Butyl-6-(ethoxymethyl)-2-methoxy-1,4-benzo-
quinone, 10b. Quinone 9a was heated in refluxing ethanol
for 6 h according to the general procedure. Oxidation and
purification by column chromatography (hexanes/ethyl
acetate, 9:1) furnished 63% of the product as a yellow oil
along with 11% of recovered starting material. IR (CDCl3)
1
1660, 1655, 1610 cmK1; H NMR (CDCl3) d 6.70 (t, JZ
4.1.17. 5-Bromo-2,3-dimethoxy-6-((trimethylsilyl)-
methyl)-1,4-benzoquinone, 14. Hydrogen bromide was
bubbled through a methylene chloride solution (100 mL) of
quinone 17, (548 mg, 1.7 mmol) for five min. Nitrogen was
then bubbled through the solution to purge any residual
HBr. The solution was poured into 10% NaHCO3, the layers
were separated and the aqueous layer extracted with
methylene chloride (3!15 mL). The solvent was evapor-
ated in vacuo and the residue re-dissolved in benzene and
treated with Ag2O (1.2 g, 5.1 mmol) and K2CO3 (700 mg,
5.1 mmol) and stirred for 1.5 h. The mixture was filtered and
concentrated in vacuo. The product was purified by flash
column chromatography (florisil, hexanes/ethyl acetate,
10:1) to give 285 mg (50%) of the product as an orange
2.1 Hz, 1H), 4.32 (d, JZ2.1 Hz, 2H), 3.98 (s, 3H), 3.59
(q, JZ7.0 Hz, 2H), 2.42 (t, JZ7.0 Hz, 2H), 1.28–1.41 (m,
4H), 1.25 (t, JZ7.0 Hz, 3H), 0.91 (t, JZ7.1 Hz, 3H); MS
(CI, rel. intens.) m/e 253 (MHC, 100), 239 (16), 209 (13);
Anal. Calcd for C14H20O4: C, 66.65; H, 7.99, found: C,
66.58; H, 8.30.
Further elution using hexanes/ethyl acetate, 2:1 gave 5% of
the symmetrical dimer 11b as a yellow oil. IR (CDCl3)
1
1670, 1655, 1605 cmK1; H NMR (CDCl3) d 6.44 (s, 2H),
3.98 (s, 2H), 2.63 (s, 4H), 2.40 (t, JZ7.2 Hz, 4H), 1.32–1.37
(m, 8H), 0.90 (t, JZ7.0 Hz, 6H); HRMS (EI, rel. intens.)
m/e calcd for C24H30O6: 414.2042, found: 414.2044; 205
(26), 177 (14), 91 (31), 55 (100).
solid: mp 54–55 8C; IR (CDCl3) 1660, 1636, 1585 cmK1
;
1H NMR (500 MHz, CDCl3) d 4.01 (s, 3H), 3.97 (s, 3H),
2.31 (s, 2H), 0.08 (s, 9H); 13C NMR (500 MHz, CDCl3) d
180.9, 176.5, 148.7, 144.4, 144.3, 128.4, 61.5, 61.2, 23.7,
K0.4; HRMS (EI, rel. intens.) m/e calcd for C12H18O4SiBr:
333.0158, found: 333.0143; 334 (0.6), 332 (0.5), 317 (0.6),
319 (0.6), 304 (1.4), 306 (1.1), 253 (2.5), 223 (1.2), 195
(0.7), 139 (3), 137 (3), 73 (100).
4.2.3. 3-n-Butyl-5-(ethoxymethyl)-2-methoxy-1,4-benzo-
quinone, 10c. According to the general procedure, 9c was
heated at reflux in absolute ethanol for 45 min. Oxidation
and purification by flash column chromatography (hexanes/
ethyl acetate, 9:1) furnished 67% of the title compound as a
yellow oil that solidified upon cooling: mp 39–40 8C; IR
(CDCl3) 1660, 1605 cmK1; 1H NMR (CDCl3) d 6.62 (t, JZ

284
J. E. Ezcurra et al. / Tetrahedron 61 (2005) 275–286
2.1 Hz, 1H), 4.33 (d, JZ2.1 Hz, 2H), 4.02 (s, 3H), 3.59
(q, JZ7.0 Hz, 2H), 2.41 (br. triplet, JZ7.1 Hz, 2H), 1.38–
1.32 (m, 4H), 1.25 (t, JZ7.0 Hz, 3H), 0.91 (t, JZ7.0 Hz,
3H); LRMS (CI, rel. intens.) m/e 253 (MHC, 100), 209 (53),
137 (36); Anal. Calcd for C14H20O4: C, 66.65; H, 7.99,
found: C, 66.51; H, 7.94.
146.4, 142.9, 141.2, 139.4, 113.5, 108.1, 81.9, 61.3, 60.9,
60.7, 60.5, 51.8, 27.9, 26.9, 0.0 (3C); IR (CDCl3) 3545,
1695, 1600 cmK1; MS (CI, rel. intens.) m/e 437
(MHC, 100), 183 (35); Anal. Calcd for C21H28O8Si: C,
57.78; H, 6.47, found: C, 57.40; H, 6.15.
Further with chloroform/methanol (1:1) followed by
oxidation of the resulting product and purification by flash
chromatography (chloroform/methanol, 97:3) gave 46% of
the symmetrical dimer 11a and 12% of the quinone 10f.
Further elution with hexanes/ethyl acetate, 2:1) gave 7% of
the symmetrical dimer 11c as a yellow oil. IR (CDCl3) 1670,
1
1650, 1605 cmK1; H NMR (CDCl3) d 6.36 (s, 2H), 4.01
(s, 6H), 2.62 (s, 4H), 2.43 (t, JZ7.0 Hz, 4H), 1.30–1.43
(m, 8H), 0.92 (t, JZ7.0 Hz, 6H); HRMS (EI, rel. intens.)
m/e calcd for C24H30O6 414.2042, found: 414.2066; 209
(38), 207 (59), 165 (41), 55 (100).
4.2.7. 5-(Acetoxymethyl)-2,3-dimethoxy-1,4-benzoqui-
none, 10g. Sodium acetate (5 equiv) and quinone 9a were
dissolved in 10 mL of acetic acid and heated at reflux for
30 min. The acetic acid was evaporated with the aid of
toluene and the residue was filtered through a short pad of
silica gel, eluted with ethyl acetate. The crude hydroquinone
was oxidized with Ag2O and purified by flash column
chromatography (hexanes/ethyl acetate, 3:1) to provide
79% of 10g as an orange solid: mp 51–52 8C; IR (CDCl3)
4.2.4. 2,3-Dimethoxy-5-(iso-propoxymethyl)-1,4-benzo-
quinone, 10d. Quinone 9a was heated in refluxing iso
propanol for 10 h according to the general procedure.
Oxidation and purification by column chromatography
(hexanes/ethyl acetate, 3:1) gave 65% of the product as a
red oil. IR (CDCl3) 1660, 1610 cmK1; 1H NMR (CDCl3) d
6.66 (t, JZ2.3 Hz, 1H), 4.32 (d, JZ2.3 Hz, 2H), 4.02
(s, 3H), 3.98 (s, 3H), 3.67 (heptet, JZ6.1 Hz, 1H), 1.19
(d, JZ6.1 Hz, 6H); LRMS (EI, rel. intens.) m/e 240
(MC, 6), 198 (38), 180 (23), 155 (25), 153 (39), 67 (100);
Anal. Calcd for C12H16O5: C, 59.99; H, 6.71: found: C,
59.63; H, 6.83.
1
1755, 1660, 1610 cmK1; H NMR (CDCl3) d 6.50 (t, JZ
1.9 Hz, 1H), 4.97 (d, JZ2.0 Hz, 1H), 4.03 (s, 3H), 4.00
(s, 3H), 2.14 (s, 3H); LRMS (CI, rel. intens.) m/e 241
(MHC, 100), 183 (63); Anal. Calcd for C11H12O6: C, 55.00;
H, 5.04, found: C, 55.10; H, 4.96. In pure acetic acid the
reaction gave 54% of 10g after 4 h at reflux.
4.2.8. 2,3-Dimethoxy-6-ethoxymethyl-5-trimethylsilyl-
1,4-benzoquinone, 18. The quinone 17 (67 mg,
0.21 mmol) was dissolved in 8 mL of absolute ethanol and
then heated to reflux for 2 h according to the general
procedure. Oxidation of the mixture followed by column
chromatography (silica gel, hexanes/ethyl acetate, 4:1) gave
17 mg (27%) of the title compound as an orange oil. IR
4.2.5. 5-(tert-Butoxymethyl)-2,3-dimethoxy-1,4-benzo-
quinone, 10e. Quinone 9a was heated in tert-butanol at
reflux for 44 h according to the general procedure.
Oxidation and purification by flash column chromatography
(hexanes/ethyl acetate, 3:1) gave 45% of the title compound
as a red oil. IR (CDCl3) 1660, 1610 cmK1 1H NMR
;
1
(CDCl3) d 6.66 (t, JZ2.3 Hz, 1H), 4.27 (d, JZ2.3 Hz, 2H),
4.02 (s, 3H), 3.98 (s, 3H), 1.23 (s, 9H); LRMS (EI, rel.
intens.) m/e 254 (MC, 1), 198 (21), 153 (24), 57 (100); Anal.
Calcd for C13H18O5: C, 61.41; H, 7.14: found: C, 61.81;
H, 7.39.
(CDCl3) 1650, 1587 cmK1; H NMR (300 MHz, CDCl3) d
4.30 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 3.52 (q, JZ7.1 Hz,
2H), 1.19 (t, JZ7.1 Hz, 3H), 0.30 (s, 9H); 13C NMR
(500 MHz, CDCl3) d 188.6, 183.3, 149.3, 148.6, 145.4,
143.8, 66.5, 63.3, 61.0, 60.9, 15.1, 0.8; HRMS CI
(rel. intens.) m/e calcd for C14H23O5Si: 299.1315, found:
299.1311, 300 (20), 299 (100), 284 (15), 283 (83), 255 (40),
183 (8).
4.2.6. Reaction of benzoquinone 9a with water. 2,3-
Dimethoxy-5-hydroxymethyl-1,4-benzoquinone, 10f.
Quinone 9a was heated in 10 mL of acetonitrile/water
(9:1) at reflux for 1.5 h. Following oxidation with Ag2O
according to the general procedure and flash column
chromatography (chloroform/methanol, 97:3) 18% of the
title compound was isolated as an orange solid: mp 72–73 8C;
IR (CDCl3) 3610, 3520, 2960, 1660, 1610 cmK1; 1H NMR
(CDCl3) d 6.61 (s, 1H), 4.53 (s, 2H), 4.03 (s, 3H), 3.99
(s, 3H), 2.10 (br s, 1H); LRMS (EI, rel. intens.) m/e 198
(MC, 12), 180 (11), 150 (17), 84 (47), 67 (67), 55 (100);
Anal. Calcd for C9H9O5: C, 54.55; H, 5.09, found: C, 54.28;
H, 5.00. In addition to 10f, 67% of the symmetrical dimer
11 a was isolated.
4.2.9. Bis(5-bromo-2,3-dimethoxy-6-methylene-1,4-ben-
zoquinone), 16 and 2-bromo-3-ethoxymethyl-5,6-
dimethoxy-1,4-benzoquinone, 15. According to the gen-
eral procedure, a solution of quinone 14 (53 mg, 0.16 mmol)
in 10 mL of absolute ethanol was heated to reflux for
20 min. Oxidation with Ag2O followed by flash column
chromatography (silica gel, hexanes/ethyl acetate, 3:1) gave
4 mg (10%) of the symmetrical dimer, 16, as an orange solid
along with 27 mg (55%) of the ethanol addition product 15
as an orange oil.
Dimer 16: mp 172–175 8C (decomp.); IR (CDCl3) 1664,
1
Reaction of quinone 9a in 95:5 acetonitrile/water for 8 h
gave 22% of xanthen 12 after flash column chromatography
(hexanes/ethyl acetate, 5:2) as a yellow solid: mp 144–145 8C;
1H NMR (CDCl3) d 6.31 (s, 1H), 5.39 (s, 1H), 3.98 (s, 6H),
3.96 (s, 3H), 3.93 (s, 3H), 3.22 (dd, JZ9.8, 6.6 Hz, 1H),
2.90 (dd, JZ16.8, 6.7 Hz, 1H), 2.85 (dd, JZ16.7, 10.0 Hz,
1H), 1.41 (d, JZ14.9 Hz, 1H), 1.33 (d, JZ14.8 Hz, 1H),
0.12 (s, 9H); 13C NMR (CDCl3) d 193.9, 193.0, 147.2,
1637 cmK1; H NMR (500 MHz, CDCl3) d 4.02 (s, 6H),
4.00 (s, 6H), 2.97 (s, 4H); 13C NMR (500 MHz, CDCl3) d
180.7, 176.4, 145.1, 144.2, 134.5, 61.6, 61.4, 28.7; HRMS
(CI, rel. intens.) m/e calcd for C18H16O881Br79Br: 519.9191,
found: 519.9224; 523 (47), 521 (62), 519 (26), 446 (14), 445
(71), 444 (25), 442 (21), 441 (40), 365 (53), 364 (23) 363
(100), 361 (21), 263 (55), 261 (54), 183 (44), 175 (47),
173 (52).

J. E. Ezcurra et al. / Tetrahedron 61 (2005) 275–286
285
Quinone 15. IR (CDCl3) 1667, 1638, 1600 cmK1; 1H NMR
(500 MHz, CDCl3) d 4.49 (s, 2H), 4.05 (s, 3H), 3.98 (s, 3H),
3.59 (q, JZ7.1 Hz, 2H), 1.21 (t, JZ7.1 Hz, 3H); 13C NMR
(500 MHz, CDCl3) d 180.3, 176.8, 145.3, 144.1, 141.3,
137.4, 67.2, 65.6, 61.5, 61.3, 15.1; HRMS (EI, rel. intens.)
m/e calcd for C11H13O5Br: 303.9947, found: 303.9968; 306
(4), 304 (4), 288 (3), 286 (3), 277 (13), 275 (14), 260 (28),
258 (22), 247 (10), 245 (9), 233 (13), 219 (6), 217 (7), 197
(10), 179 (6), 119 (32), 117 (34), 66 (80), 53 (100).
measurements. The relative concentration of the reactant
was taken to be the fraction of the initial standardized
measurement (time 0Z1.00). The natural log of the relative
concentration was plotted against time. The kobs was found
from the slope of the line and the half life for the reaction
was found by dividing the natural log of 2 by kobs. An
alternate procedure was required for the measurement of the
reaction rate of the triphenylsilyl-substituted quinone 9d
due to the low solubility in ethanol. In this case, a solution of
40 mg of quinone 9d was dissolved in 50 mL of absolute
ethanol and heated to 70 8C in a jacketed flask equipped
with a circulating bath. 20 mL of toluene was added to the
solution to act as an internal standard. Samples of the
solution were taken approximately every 3 h and diluted
with acetonitrile for analysis by HPLC. A Hewlett–Packard
HP 1050 equipped with a YMC ODS-AQ column was used
for the analysis. The mobile phase consisted of acetonitrile/
4.2.10. ((2-Anthracenethio)ethyl)-4-hydroxy-3-methoxy-
4-((3-trimethylsilyl)-1-propynyl)-2-cyclobuten-1-one, 30.
To a cooled (K78 8C) solution of propargyltrimethylsilane
(0.15 mL, 0.9 mmol) in 10 mL of dry THF was added
n-BuLi (0.83 mmol) via syringe. The resulting solution was
stirred for 5 min at K78 8C and then added via cannula to a
cold solution of cyclobutenedione15 29 (200 mg,
0.58 mmol) in 40 mL of dry THF. Aqueous work-up after
five min gave the crude product as a yellow oil. Purification
by radial chromatography (silica gel, hexanes/ethyl acetate,
8:2) afforded 157 mg (63%) of the title product as an orange
oil. IR (neat) 3308, 1758, 1622 cmK1; 1H NMR (500 MHz,
CDCl3) d 8.93 (d, JZ8.9 Hz, 2H), 8.44 (s, 1H), 7.98 (d, JZ
8.4 Hz, 2H), 7.60–7.57 (m, 2H), 7.50–7.47 (m, 2H), 4.4 (br
s, 1H), 4.02 (s, 3H), 3.09 (m, 2H), 2.18 (m, 2H), 1.58 (s, 2H),
0.08 (s, 9H); 13C NMR (500 MHz, CDCl3) d 187.9, 181.6,
134.6, 131.6, 128.9, 128.8, 128.2, 126.9, 126.6, 126.0,
125.2, 89.7, 82.7, 73.1, 59.3, 33.2, 22.9, 7.4, K2.1; HRMS
(EI, rel. intens.) m/e calcd for C27H28O3SSi: 460.1528,
found: 460.1546; 462 (12), 461 (10), 460 (54), 325 (13), 252
(31), 251 (100), 210 (12), 179 (19), 178 (19), 165 (17), 161
(16), 73 (57).
1
water containing 0.1% phosphoric acid. As with the H
NMR experiments, the peak area of the starting material was
divided by the peak area of the toluene peak to standardize
the measurement. The relative concentration of quinone 9d
was calculated in the same manner as the other quinones
studied by NMR.
4.4. Procedure for the study of quinone 31 with
supercoiled DNA
Ten microliters of a solution of 2 mg of quinone 31 in 1 mL
of CHCl3 was put into a microfuge tube. The solution was
then concentrated to dryness in vacuo. To the residue was
added 1.1 mL of FX174 supercoiled DNA and 18.9 mL of
TE buffer (10 mM tris$HCl, 1mM EDTA, pH 7.2). The
mixture was incubated at 51 8C for 21 h. The samples which
contained ethidium bromide were composed of 10 mL of an
ethidium bromide solution (1.4 mL of ethidium bromide in
28.6 mL of TE buffer), 1.1 mL of DNA and 8.9 mL of TE
buffer. After the incubation, the mixtures were cooled to
0 8C and 2 mL of a loading buffer (0.25% bromophenol blue,
40% (w/v) sucrose in water) was added. A 7 mL portion of
this mixture was loaded onto a 1% agarose gel and
developed for 1 h at 101 V.
4.2.11. 2-Methoxy-3-(2-anthracenethio)ethyl)-5-((tri-
methylsilyl)methyl)-1,4-benzoquinone, 31. A solution of
30 (129 mg, 0.28 mmol) in 10 mL of acetonitrile was heated
to reflux for 1 h. The solution was cooled to room
temperature and the solvent was removed in vacuo.
Purification by radial chromatography (silica gel, hexanes/
ethyl acetate, 10:1) yielded 82 mg (64%) of the title
compound as a bright red oil. IR (neat) 1644, 1598,
1
1516 cmK1; H NMR (500 MHz, CDCl3) d 8.91 (d, JZ
8.8 Hz, 2H), 8.46 (s, 1H), 8.00 (d, JZ8.5 Hz, 2H), 7.6–7.46
(m, 4H), 6.12 (s, 1H), 3.66 (s, 3H), 2.96 (m, 2H), 2.64
(m, 2H), 1.89 (s, 2H), K0.04 (s, 9H); 13C NMR (500 MHz,
CDCl3) d 186.9, 183.1, 155.4, 149.6, 134.4, 131.7, 129.2,
128.92, 128.89, 128.79, 127.6, 126.9, 126.5, 125.2, 60.6,
35.2, 24.0, 21.1, K1.6; HRMS (CI, rel. intens.) m/e calcd
for C27H31O3SiS: 463.1763, found: 463.1695; 464 (15), 163
(100), 461 (28), 255 (15), 253 (35), 211 (39), 179 (79), 112
(21), 97 (25), 95 (19), 91 (28), 85 (50), 83 (34), 81 (47).
Acknowledgements
The authors wish to thank the National Institutes
(GM-36312) of Health for financial support of this work
and SmithKline Beecham for a generous gift of squaric acid.
References and notes
4.3. General procedure for the measurement of reaction
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